1. Field of the Invention
The present invention relates to pharmaceutical compositions containing an active agent having a modality of action whereby sympathetic neuron terminals are stimulated and l-norepinephrine is released and to methods for treating glaucoma, nasal congestion, chest congestion, etc. using such compositions.
2. The Prior Art
Glaucoma is a term used to describe various eye disorders resulting from excessive intraocular pressure. Intraocular pressure is maintained at specific levels by a combination of two factors: (1) the rate at which aqueous humor is formed and (2) the rate at which aqueous humor leaves the eye. If the rate at which aqueous humor is formed can be reduced, then a decrease in eye pressure should be anticipated. Likewise, if the rate of aqueous humor outflow can be increased, the eye pressure should again decline.
Earlier reports have indicated that drugs of many modalities of action were able to lower eye pressure of glaucomatous patients. Such drugs include .alpha.-adrenergic agonists, .beta.-adrenergic agonists, .beta.-adrenergic blockers, p-sympathomimetic agonists and carbonic anhydrase inhibitors. Agents included in all of these groups have been reported to decrease the rate of aqueous humor formation in the eye.
In a previously published article "The Formation and Inhibition of Aqueous Humor Production", Archives of Ophthalmology, Vol. 96, September 1978, pp. 1664-1667, the present applicant and S. J. Cevario disclosed data indicating that certain sympathomimetic agents, acetazolamide (a carbonic anhydrase inhibitor) and ouabain (a cardiac glycoside) operate as vasoconstrictors to inhibit aqueous humor production through a mechanism by which the drugs stimulate intraocular receptors "E-1" which, in turn, communicate with neuronal terminals where norepinephrine is released for the stimulation of adjoining .alpha.-adrenergic receptor sites. All drugs operating by such a mechanism may be considered "norepinephrine releasers".
Among the sympathomimetic agents, epinephrine is perhaps most widely used in the treatment of chronic simple (wide-angle) glaucoma. However, several problems are commonly encountered in the treatment of glaucoma with epinephrine compositions. The drug is not always continuously effective. Prolonged use of epinephrine in the 1-4% concentrations of commercial ophthalmic solutions leads to pigmentation (sedimentation of the oxidized drug) and maculopathy. Moreover, narrow-angle glaucoma is a contraindication for epinephrine because, in commercial concentrations, epinephrine produces dilation of the pupil which further narrows the angle thereby exacerbating the condition.
Various sympathomimetic drugs, have also been used in commercially available preparations for the relief of nasal and chest congestion. In addition to finding utility in ophthalmic solutions for the treatment of simple ("open-angle" or "wide-angle") glaucoma, epinephrine has been used as the active agent (bronchodilator) in sprays for the temporary relief of the paroxysms of bronchial asthma. Phenylephrine has also been used in tablets and syrups and topical sprays for the relief of nasal and chest congestion, as well as in the treatment of glaucoma. Ephedrine finds extensive use as a bronchodilator in tablets, syrups and topical mists. In conventional pharmaceutical preparations these compounds are most commonly used in salt form, e.g., hydrochloride, hydrobromide, bitartrate or tannate.
One of the problems with the clinical use of the above mentioned drugs is that, within time, tachyphylaxis develops, i.e., the drugs become ineffective or remain only moderately effective. For example with regard to epinephrine, Remington's Pharmaceutical Sciences (16th Ed. 1980), p. 824 states "As a topical decongestant it causes too much aftercongestion to be a first-line drug."
l-norepinephrine is a hormone which naturally occurs in the human body and is the essential neuro transmitter of sympathetic activity in the peripheral nervous system. l-norepinephrine, also known as levarterenol, l-noradrenaline and l-arternal, is classified as an .alpha.-adrenergic agonist and its chief physiological function is that of vasoconstriction. The chief medical uses of l-norepinephrine are in the treatment of hypotension and shock due to impaired vasomotor activity.
Norepinephrine has been considered to have no clinical value in the treatment of glaucoma on the basis of findings that it has negligible effect in reducing ocular tension. Duke-Elder, System of Ophthalmology, Vol. XI, p. 518. Gaasterland et al in "Studies of Aqueous Humor Dynamics in Man", Investigative Ophthalmology, Vol. 12, No. 4, April 1973, pp 267-279, disclose the results of studies of the effects on aqueous humor dynamics in humans using a 2% sterile solution of norepinephrine as an alpha-adrenergic stimulator, a 1% sterile solution isoproterenol hydrochloride as a beta-adrenergic stimulator, a 2% sterile solution of l-epinephrine bitartrate (an alpha and beta stimulator) and a combination of the norepinephrine and isoproterenol solutions. The combination provided an effect described as similar to that achieved with epinephrine which is both an alpha and beta agonist. The study concluded that "the acute effect of epinephrine in young normal subjects is comprised of two parts--reduction of aqueous flow due to beta-adrenergic receptor stimulation and reduction of pseudofacility due to alpha-adrenergic receptor stimulation, and that the reduction of intraocular pressure is secondary to the addition of these two effects." A comparison of the data of Gaasterland et al for the combined use of isoproterenol and norepinephrine with that for isoproterenol alone indicates that the use of norepinephrine inhibited the effectiveness of isoproterenol in lowering aqueous humor production and intraocular pressure. Administration of norepinephrine alone produced "no significant change" in intraocular pressure and produced an increase in aqueous flow.